A current perspective on cancer immune therapy: Step‑by‑step approach to constructing the magic bullet

Immunotherapy is the new trend in cancer treatment due to the selectivity, long lasting effects, and demonstrated improved overall survival and tolerance, when compared to patients treated with conventional chemotherapy. Despite these positive results, immunotherapy is still far from becoming the perfect magic bullet to fight cancer, largely due to the facts that immunotherapy is not effective in all patients nor in all cancer types. How and when will immunotherapy overcome these hurdles? In this review we take a step back to walk side by side with the pioneers of immunotherapy in order to understand what steps need to be taken today to make immunotherapy effective across all cancers. While early scientists, such as Coley, elicited an unselective but effective response against cancer, the search for selectivity pushed immunotherapy to the side in favor of drugs focused on targeting cancer cells. Fortunately, the modern era would revive the importance of the immune system in battling cancer by releasing the brakes or checkpoints (anti-CTLA-4 and anti-PD-1/PD-L1) that have been holding the immune system at bay. However, there are still many hurdles to overcome before immunotherapy becomes a universal cancer therapy. For example, we discuss how the redundant and complex nature of the immune system can impede tumor elimination by teeter tottering between different polarization states: one eliciting anti-cancer effects while the other promoting cancer growth and invasion. In addition, we highlight the incapacity of the immune system to choose between a fight or repair action with respect to tumor growth. Finally we combine these concepts to present a new way to think about the immune system and immune tolerance, by introducing two new metaphors, the “push the accelerator” and “repair the car” metaphors, to explain the current limitations associated with cancer immunotherapyThis work was supported by NIH R00 CA154605 and Louisiana Board of Regents LEQSF(2016-17)-RD-C-14 (H.L.M.), a Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (B.S.Jr) and a Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY (B.S.Jr)

Biophysical suitability, economic pressure and land-cover change: a global probabilistic approach and insights for REDD+

There has been a concerted effort by the international scientific community to understand the multiple causes and patterns of land-cover change to support sustainable land management. Here, we examined biophysical suitability, and a novel integrated index of “Economic Pressure on Land” (EPL) to explain land cover in the year 2000, and estimated the likelihood of future land-cover change through 2050, including protected area effectiveness. Biophysical suitability and EPL explained almost half of the global pattern of land cover (R 2 = 0.45), increasing to almost two-thirds in areas where a long-term equilibrium is likely to have been reached (e.g. R 2 = 0.64 in Europe). We identify a high likelihood of future land-cover change in vast areas with relatively lower current and past deforestation (e.g. the Congo Basin). Further, we simulated emissions arising from a “business as usual” and two reducing emissions from deforestation and forest degradation (REDD) scenarios by incorporating data on biomass carbon. As our model incorporates all biome types, it highlights a crucial aspect of the ongoing REDD + debate: if restricted to forests, “cross-biome leakage” would severely reduce REDD + effectiveness for climate change mitigation. If forests were protected from deforestation yet without measures to tackle the drivers of land-cover change, REDD + would only reduce 30 % of total emissions from land-cover change. Fifty-five percent of emissions reductions from forests would be compensated by increased emissions in other biomes. These results suggest that, although REDD + remains a very promising mitigation tool, implementation of complementary measures to reduce land demand is necessary to prevent this leakage

Attitudes towards treatment among patients suffering from sleep disorders. A Latin American survey

BACKGROUND: Although sleep disorders are common, they frequently remain unnoticed by the general practitioner. Few data are available about the willingness and reasons of patients with sleep disturbances to seek for medical assistance. METHODS: The results of a cross-sectional community-based multinational survey in three major Latin American urban areas, i.e. Buenos Aires, Mexico City and Sao Paulo, are reported. Two-hundred subjects suffering sleep disturbances and 100 non-sufferers were selected from the general population in each city (total number: 600 sufferers vs. 300 non-sufferers). A structured interview was conducted, sleep characteristics, feelings about sleep disturbances and strategies to cope with those problems being recorded. Data were analyzed by employing either t-test or analysis of variance (ANOVA) to the Z-transformed proportions. RESULTS: 22.7 ± 3.5 % (mean ± SEM) of subjects reported to suffer from sleep disturbances every night. About 3 out of 4 (74.2 ± 2.0 %) considered their disorder as mild and were not very concerned about it. Only 31 ± 2 % of sufferers reported to have sought for medical help. Although 45 ± 2 % of sufferers reported frequent daily sleepiness, trouble to remember things, irritability and headaches, they did not seek for medical assistance. Among those patients who saw a physician with complaints different from sleep difficulties only 1 out of 3 (33 ± 2 % of patients) were asked about quality of their sleep by the incumbent practitioner. Strategies of patients to cope with sleep problems included specific behaviors (taking a warm bath, reading or watching TV) (44 ± 1.6 %), taking herbal beverages (17 ± 1.2 %) or taking sleeping pills (10 ± 1.1 %). Benzodiazepines were consumed by 3 ± 0.6 % of sufferers. CONCLUSION: Public educational campaigns on the consequences of sleep disorders and an adequate training of physicians in sleep medicine are needed to educate both the public and the general practitioners about sleep disorders

Estrogen receptor beta expression in prostate adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and there are many studies recently done, showing that prostate cancer growth is also influenced by estrogen. The characterization of estrogen receptor beta (ER-b) brought new insight into the mechanisms underlying estrogen signalling. In the present study, we investigated the expression of estrogen receptor-b (ER-b) in human prostate cancer tissues.</p> <p>Methods</p> <p>We selected 52 paraffin-embedded blocks of prostate needle biopsies in a cross-sectional study to determine frequency and rate of ER-b expression in different grades of prostate adenocarcinoma according to Gleason grading system. Immunohistochemical staining of tissue sections by monoclonal anti ER-b antibody was performed using an Envision method visualising system.</p> <p>Results</p> <p>ER-b expression was seen in tumoral cells of prostatic carcinoma in all 29 cases with low and intermediate tumors (100%) and 19 of 23 cases with high grade tumor (83%). Mean rate of ER-b expression in low & intermediate grade cancers was 68.41% (SD = 25.63) whereas high grade cancers showed 49.48% rate of expression (SD = 28.79).</p> <p>Conclusions</p> <p>ER-b expression is reduced in high grade prostate cancers compared to low & intermediate grade ones (<it>P </it>value 0.027).</p

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

Reproductive and hormonal factors and mortality among women with colorectal cancer in the NIH-AARP Diet and Health Study

BACKGROUND: Although use of menopausal hormone therapy (MHT) and some reproductive factors have been associated with colorectal cancer (CRC) risk, relations between these factors and survival after CRC diagnosis are unclear. METHODS: Among 2053 post-menopausal women diagnosed with incident CRC in the NIH-AARP Diet and Health Study, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards regression to test associations between oral contraceptive (OC) use, menarche age, age at first birth, parity, menopausal age, and MHT use with all-cause and CRC-specific mortality. RESULTS: There were 759 deaths (332 CRC-related deaths) over a median follow-up of 7.7 years. We observed no statistically significant associations between OC use, menarche age, age at first birth, parity, menopausal age, and mortality. Compared with never MHT use, former use was not associated with mortality, but we found an inverse association among baseline current users, for both all-cause (HR=0.79, 95% CI 0.66–0.94) and CRC mortality (0.76, 0.59–0.99). CONCLUSION: Future studies should further focus on the mechanisms by which exogenous oestrogen exposure might affect tumour progression and CRC survival

How important is the context of an adolescent's first alcoholic drink? Evidence that parental provision may reduce later heavy episodic drinking

Objective: This study examined the extent to which a retrospective measure of parental provision of the first alcoholic beverage was related to current heavy episodic drinking and current responsible drinking practices. Sample: 608 14- to 17-year-olds from the 2007 Australian National Drug Strategy Household Survey. Measures: Source of first alcoholic beverage (friends/parents/others), source of current alcohol, age of onset of alcohol use, current responsible drinking practices, and proportion of current friends who drink. Results: Binary logistic and multiple regression procedures revealed that parental provision of an adolescent's first alcoholic beverage predicted lower current heavy episodic drinking, and responsible drinking mediated this association. Discussion: The results suggested that for adolescents who become alcohol users, parental provision of the first drink may reduce subsequent alcohol-related risks compared to introduction to alcohol by friends and other sources. Alcohol-related risks remain significant for adolescents who consume alcohol, independent of who is the provider. Copyright (C) 2012 S. Karger AG, Base

The environmental impact of fertilizer embodied in a wheat-to-bread supply chain

Food production and consumption cause approximately one-third of total greenhouse gas emissions, and therefore delivering food security challenges not only the capacity of our agricultural system, but also its environmental sustainability. Knowing where and at what level environmental impacts occur within particular food supply chains is necessary if farmers, agri-food industries and consumers are to share responsibility to mitigate these impacts. Here we present an analysis of a complete supply chain for a staple of the global diet, a loaf of bread. We obtained primary data for all the processes involved in the farming, production and transport systems that lead to the manufacture of a particular brand of 800 g loaf. The data were analysed using an advanced life cycle assessment (LCA) tool, yielding metrics of environmental impact, including greenhouse gas emissions. We show that more than half of the environmental impact of producing the loaf of bread arises directly from wheat cultivation, with the use of ammonium nitrate fertilizer alone accounting for around 40%. These findings reveal the dependency of bread production on the unsustainable use of fertilizer and illustrate the detail needed if the actors in the supply chain are to assume shared responsibility for achieving sustainable food production